Figure 1 Hepatitis B virus life cycle. Hepatitis B virus (HBV) enters hepatocytes via interaction with the heparan sulfate proteoglycan (HSPG), followed by the sodium taurocholate co-transporting polypeptide (NTCP) receptor. The virus envelope and the hepatocytes’ membrane merge, releasing the nucleocapsid into the cytoplasm. The viral genome is transferred to the nucleus after the capsid is removed. The relaxed circular genome is restored in the nucleus, resulting in covalently closed circular DNA (cccDNA), and viral DNA could be integrated into the host DNA. Integrated viral DNA is a constant source of hepatitis B surface antigen (dashed line). The cccDNA is a template for pregenomic RNA (pgRNA) production and the transcription of all viral mRNAs. In addition, the cccDNA is associated with host factors and cellular histones, and forms a minichromosome. The core proteins are constructed into nucleocapsids together with pgRNA. Viral polymerase converts the pgRNA to relax circular DNA, resulting in a mature nucleocapsid. The core particles can recycle and replenish cccDNA (dashed line), or gather with the envelope proteins in the endoplasmic reticulum and Golgi, and enter the secretory pathway. Through the secretory process, virions gain surface antigens and are secreted as infectious virions-Dane particles. Also, incomplete subviral particles are secreted, such as spheres and filaments lacking nucleocapsid proteins. HSP: Heparan sulfate proteoglycan; NTCP: Sodium taurocholate co-transporting polypeptide receptor; cccDNA: Covalently closed circular DNA; pgRNA: Pregenomic RNA; HBx: Hepatitis B protein X; HBsAg: Hepatitis B surface antigen; HBe: E antigen; ER: Endoplasmatic reticulum.

Figure 2 Role of circadian rhythm genes in liver metabolism. BMAL1: Brain and muscle ARNTL-like protein 1; CLOCK: Circadian locomotor output cycles kaput; PPAR: Peroxisome proliferator-activated receptors; CRY: Cryptochrome; PER: Period; ROR: Retinoic acid receptor-related orphan receptor; cAMP: Cyclic adenosine monophosphate; AMPK: AMP-activated protein kinase; PGC1α: PPAR coactivator 1α.

Figure 3 Relationship between circadian rhythm genes and hepatitis B virus replication. Gray dashed lines indicate normal circadian rhythm in hepatocytes. Black arrows show the association between core clock proteins and hepatitis B virus (HBV) entry into hepatocytes and its replication. Increased levels of REV-ERB protein prevent the entry of HBV into hepatocytes by impaired action on the sodium taurocholate co-transporting polypeptide (NTCP) receptor. Brain and muscle ARNTL-like protein 1 (BMAL1) protein binds HBV DNA and thus controls viral genome expression and the formation of new viral particles. In infected hepatocytes, REV-ERB through HNF4α mediator increases pregenomic RNA (pgRNA) transcription, while HNF4α inhibits BMAL1 expression, promoting HBV replication. Red arrows indicate circadian rhythm genes inhibited by hepatitis B protein X (HBx) protein (BMAL1, CRY1, CRY2, and PER3). Conversely, HBx increases CLOCK, PER1, PER2, and RORγ gene expression (indicated by blue arrows). Increased expression of RORγ leads to the proliferation of hepatoma cells. BMAL1: Brain and muscle ARNTL-like protein 1; cccDNA: Covalently closed circular DNA; CCG: Clock-controlled genes; CLOCK: Circadian locomotor output cycles kaput; CK1: Casein kinase 1; CRY: Cryptochrome; HBx: Hepatitis B protein X; HNF4α: Hepatocyte nuclear factor 4 alpha; HSP: Heparan sulfate proteoglycan; NTCP: Sodium taurocholate co-transporting polypeptide receptor; PER: Period; pgRNA: Pregenomic RNA; ROR: Retinoic acid receptor-related orphan receptor; RORE: ROR element.